Superantigens are pathogen-derived proteins that bind to TCR V beta elements and MHC class II molecules and induce powerful T cell proliferative responses. In many respects, these responses resemble those to conventional peptide antigens; nonetheless there are subtle and interesting differences. CD4+ T cell responses to viral-encoded MIsa antigens fail to generate typical T cell memory, show a preferential TH1 cytokine profile and are associated in vivo with the ultimate elimination of the majority of responding T cells. Preliminary date suggest that the response to MIsa antigens is unusually dependent on particular accessory molecule interactions, such as those involving CD40L/CD40 and LFA-1/ICAM-1. In addition, early TCR-mediated signal transduction events induced by MIsa antigens are atypical and characterized by poor phosphorylation of CD3 components and zetu polypeptides. In this application, experiments are proposed to test the working model that the unusual structural features of TCR recognition of MIsa antigens leads to atypical early TCR signal transduction events and places constraints on the accessory molecules regulating the response. Aim 1 is directed to characterizing the role of the accessory molecules involved in regulating MIsa responses with particular emphasis on the mechanisms involved in CD40 and ICAM-1 mediated events. Aim 2 deals with further defining the signal transduction events involved in MIsa-specific T cell activation and contrasting these events with those involved in conventional peptide-specific responses. Information will be sought regarding the role of accessory molecules in modifying or compensating the atypical MIsa specific TCR signaling events. Studying T cell responses to superantigens is important because these antigens serve as useful models for defining alternative pathways for T cell activation. In addition, superantigens are associated with an increasing number of bacterial and viral microorganisms and are likely to contribute to the pathogenicity of those agents.